Key Facts

Thalassaemias are inherited haemoglobinopathies characterised by reduced synthesis of globin chains, leading to ineffective erythropoiesis, haemolysis, and anaemia.

Epidemiology

• Most common single-gene disorder worldwide
• β-thalassaemia: Mediterranean, Middle East, South/Southeast Asia
• α-thalassaemia: Southeast Asia, Southern China, Africa
• UK: ~1,000 patients with transfusion-dependent thalassaemia; ~30,000 carriers

Aetiology

β-thalassaemia:

• 200 point mutations in β-globin gene (chromosome 11)

• β⁰: no β-globin production; β⁺: reduced production
• Trait (heterozygous): one abnormal allele
• Major (homozygous β⁰/β⁰ or β⁰/β⁺): severe; transfusion-dependent
• Intermedia: moderate; variable transfusion need

α-thalassaemia:

• Gene deletions on chromosome 16 (4 α-globin genes total: 2 per chromosome)
• 1 deletion: silent carrier
• 2 deletions: α-thal trait (mild microcytosis)
• 3 deletions: HbH disease (moderate haemolytic anaemia)
• 4 deletions: Hb Bart's hydrops fetalis (incompatible with life)

Pathophysiology

• Imbalance in globin chain production → excess unpaired chains precipitate → oxidative damage to RBCs
• β-thal: excess α-chains → ineffective erythropoiesis + haemolysis
• Ineffective erythropoiesis → massive marrow expansion → skeletal deformity
• Increased iron absorption (due to suppressed hepcidin) + transfusion → iron overload

β-Thalassaemia Trait

• Usually asymptomatic; mild microcytic anaemia
• Discovered incidentally on FBC (disproportionately low MCV for Hb level)
• Important to identify for genetic counselling

β-Thalassaemia Major

• Presents at 6–12 months (after HbF declines)
• Severe anaemia, failure to thrive
• Hepatosplenomegaly (extramedullary haematopoiesis)
• Skeletal changes: frontal bossing, maxillary hyperplasia ('chipmunk facies'), 'hair on end' skull X-ray
• Growth retardation, delayed puberty
• Without treatment: death in first decade

β-Thalassaemia Intermedia

• Variable severity between trait and major
• May or may not require regular transfusion

α-Thalassaemia

• Silent carrier/trait: usually asymptomatic
• HbH disease: moderate haemolytic anaemia, splenomegaly
• Hb Bart's: fatal hydrops fetalis in utero

Red Flags

• Severe anaemia in infancy (transfusion-dependent)
• Iron overload complications (cardiac, hepatic, endocrine)
• Non-immune hydrops fetalis (Hb Bart's)

Bloods

• FBC: microcytic hypochromic anaemia; very low MCV for degree of anaemia (often MCV <70 fL with near-normal Hb in trait)
• Blood film: target cells, microcytes, hypochromia; nucleated RBCs in major
• Reticulocyte count: raised
• Iron studies: normal or raised ferritin and transferrin saturation (distinguishes from IDA)
• Hb electrophoresis/HPLC: KEY diagnostic test
  • β-thal trait: HbA2 >3.5% (usually 4–6%)
  • β-thal major: HbF 60–90%, HbA absent or very low, HbA2 variable
  • HbH disease: HbH (β4 tetramers) on electrophoresis

Special Tests

• Genetic testing: definitive diagnosis (prenatal counselling)
• Ferritin: monitor iron overload in transfused patients
• Cardiac MRI T2*: gold standard for myocardial iron overload (<20ms = iron loading; <10ms = severe)
• Liver MRI (FerriScan): liver iron concentration
• Endocrine: glucose, TFTs, gonadotrophins (iron overload endocrinopathy)

β-Thalassaemia Trait

• No treatment needed
• Genetic counselling for couples at risk
• Do NOT give iron (not iron-deficient)

β-Thalassaemia Major

Chronic transfusion:

• Regular RBC transfusions every 2–4 weeks
• Aim pre-transfusion Hb >95–100 g/L
• Suppresses ineffective erythropoiesis and prevents skeletal deformity

Iron chelation (ESSENTIAL):

• Deferasirox 14–28mg/kg/day oral (first-line; NICE TA376)
• Desferrioxamine 20–50mg/kg SC/IV over 8–12 hours, 5–7 nights/week: highly effective but burdensome
• Deferiprone 75mg/kg/day oral: especially for cardiac iron
• Target ferritin <1000 µg/L; cardiac MRI T2* >20ms

Supportive:

• Folic acid 5mg daily
• Hepatitis B vaccination (before transfusion)
• Endocrine monitoring and replacement (growth hormone, sex hormones, thyroxine)
• Bone densitometry

Curative

• Allogeneic stem cell transplant: curative; ~90% success in children <14 with matched sibling donor
• Gene therapy: betibeglogene autotemcel (Zynteglo; NICE HST24) — one-time gene therapy for β-thal
• Luspatercept: reduces transfusion burden in thal intermedia/major (BELIEVE trial; NICE TA872)

Referral Criteria

• Specialist haemoglobinopathy centre: all thalassaemia major/intermedia
• Genetic counselling: all carriers and affected families
• Prenatal diagnosis: CVS or amniocentesis if both parents carriers

• β-thal major without treatment: death in first decade
• With modern transfusion + chelation: median survival >50 years (improving)
• Leading cause of death: cardiac iron overload (cardiac failure, arrhythmia)
• SCT: ~90% cure rate; ~5% transplant-related mortality
• Thal trait: normal life expectancy; no treatment needed
• Quality of life: significantly impacted by transfusion burden and chelation

α-Thalassaemia by Gene Deletion